Benzothiazole derivatives

ABSTRACT

New benzothiazole derivatives and the salts thereof have excellent .beta.-adrenergic receptor blocking activity and antiarrhythmic effects. A process for producing the benzothiazole derivatives and their salts is also described.

United States Patent [1 1 Kasuya et al.

[ Apr. 8, 1975 Contin uution-in-p I973, abandoned.

Field of Search BENZOTHIAZOLE DERIVATIVES Inventors: Yutaka Kasuya, Kawasaki; Hiroyuki Obase, Osaka, both of Japan Assignee: Kyowa Hakko Kogyo Co.. Ltd.,

Tokyo. Japan Apr. I2, 1973 App]. No.: 350,480

Related US. Application Data art of Ser. No. 345.108. March 26,

US. Cl. 260/304; 424/200; 424/232;

Int. Cl

References Cited UNITED STATES PATENTS McLoughlin et ul. 260/304 Heart rate (beats/min) OTHER PUBLICATlONS Wagner et 21].. Synthetic Organic Chemistry, N.Y., John Wiley & Sons, I953. pp. 226-228 & 660-665.

Primary Examiner-Richard J. Gallagher Armrney, Agent. or Firm-Fitzpatrick, Cella. Harper & Scinto [57] ABSTRACT New benzothiazole derivatives and the salts thereof have excellent ,B-adrenergic receptor blocking activity and anti-arrhythmic effects. A process for producing the benzothiazole derivatives and their salts is also described.

7 Claims, 4 Drawing Figures 0' Dose isoproterenol (M) PMENTEDAPR 8 i975 FIG.1

AE EHmwQV 3m; 3mm:

7) M m( m n a m O@ 1.1.. O r p O 4 S O. 9 S O D 0 0 2 FIG.2

0* Dose isoproterenol (M) E BE QV 9m: mw:

BENZOTHIAZOLE DERIVATIVES This application is a continuation-in-part of L'.S. ap plication Ser. l\o. 345.108. filed Mar. 26. N73. and novv abandoned.

This invention relates to nevv bemothiazole derivatives and the salts thereof and to methods for preparing same. The benzothiazole derivatives and their salts show strong pharmacological activity. especially [:i-adrenergic receptor blocking activity and. therefore. are useful in the treatment or prevention of nervous disorders.

The benzothiazole derivatives which are the subject of the present invention are new compounds and are represented by the formula wherein R represents a hydrocarbon group having 1 to carbon atoms such as an alkyl group having 1 to 5 carbon atoms. such as a methyl. ethyl. propyl. isopropyl. butyl. sec-butyl. isobutyl. n-amyl or isoamyl group. an aralkyl group having 7 to l() carbon atoms. such as a benzyl group or lmethyl-f -phenylpropyl group. or an aryl group having 6 to ll) carbon atoms. such as a phenyl group or naphthyl group.

The benzothiazole derivatives may also be employed in the form ofa salt. Suitable salts are the acid addition salts such as. for example. the salts of inorganic acids such as the hydrochloride. hydrobromide. phosphate. sulfate and nitrate and the organic acid salts. particularly aliphatic and aromatic carboxylic acid salts including oxycarboxylic acid salts and especially mono-, di-. and tricarboxylic acid salts. preferably C C,., aliphatic carboxylic acid salts and -C aromatic carboxylic acid salts. such as the oxalate. lactate. tartrate. acetate. propionate. salicylate. citrate. maleate. adipate. naphthoate. succinate and benzoate.

In accordance with the present invention. a process for the preparation of the desired benzothiazole derivative is also provided. The desired compounds may be prepared by reacting a compound represented by the formula m 5 OCH2C\H/CH2 s ocn cacn x b Ill wherein X represents a halogen atom such as chlorine. bromine or iodine. or a leaving group such as -oso 0SO CH -o-c-ca -OCSCH ll ll S and the like with an amine represented by the formula NH R wherein R has the same significance as defined above. Examples of suitable amines are niethylaniine. ethy lamine. propylamine. isopropy lamine. butylaniinc. isobutylaminc. benzylaminc. B-phcnylethylamine and l-methyl-3-phenylpropylainine. The amount of an amine employ ed in the reaction is preferably ten-fold excess.

The reaction may be carried out at a temperature of to IZUC. preferably to C for 2 to o hours. The reaction can be carried out in the presence or absence of a solvent. Where a solvent is employed. organic solvents such as benzene. toluene. ethanol. chloroform. and the like may be employed. In general. any solvent that does not participate in the reaction may be employ ed. Where the reaction is carried out in the absence of a solvent. the reactants are heated at a temper ature betvveen 50 and C. The dry reaction is prel erably carried out in an autoclave with heating. After the reaction. the solvent and excessive amine are removed by distillation. The desired product can be ob tained by extraction of the residue with a suitable solvent. for example. ethyl acetate. The compound of the formula (ll used as the starting material may be prc pared by reacting (i-hydroxybenzothiazole \vith epi chlorohydrin in the presence of alkali. The starting material of the formula (lb. may be prepared by cleaving the epoxy ring of the compound of the formula II)...

For example. the epoxy compound (1),. is heated with lN-HCl and the mixture is poured into a large amount ofvvater. The liberated oil is extracted with ether. Distilling off the ether from the extract. a compound tl),, where X. is Cl is obtained. Where a compound (l),,

where is desired. an alcoholic solution of the compound (I),, is heated with an aqueous solution of p-toluene sulfonic acid on water bath for 2 to 3 hours and the resulted mixture is treated as above.

The desired benzothiazole derivatives can also be prepared by reacting 6-hydroxybenzothiazole with a compound represented by the formula X 1S -OSO XCH CHCH mm or ca CH(IH NHR 2 t 2 2 The benzothiazole derivatives can further be prepared by hydrogenolyzing a compound represented by the formula wherein R has the same significance as defined above. in the presence of a reducing catalyst such as palladium carbon. platinum. nickel. nickel alloy. etc. in a suitable solvent. The reaction can be carried out at a temperature of It)" to 125C. preferably ll to 70C under an mospheric pressure or under applied pressure. Any solvent usually used in catalytic reduction reactions such as methanol. ethanol. propanol. benzene. toluene. chloroform. dio\ane. etc. can be employ ed. The reaction is generally carried out until the theoretical amount of hydrogen has been absorbed.

The raw material compound of the formula (ll) may be prepared by reacting the compound of the formula lll,, or (1),, with a benzylamine represented by the formula RNH-CH wherein R has the same significance as defined above. at 5tl to lZtlC for I to 6 hours using a suitable solvent.

Alternatively. the benzothiazole derivatives can be prepared by reacting a compound represented by the formula together with an alkanal or alkanone having l to 10 carbon atoms under reduction conditions. Alkanals such as formaldehyde, acetaldehydc. propionaldehyde. butyraldehyde. isobutyraldehyde. n-amylaldehyde and ismmiylaldehyde may be employed Alkanones such as acetone. methyl ethyl ketone. methyl n-propyl ketone and diethyl ketone may be employed.

The reaction can be carried out under atmospheric pressure or under applied pressure with heating and stirring in the presence of hydrogen and a suitable cata lyst. Alternatively. the reaction can be carried out in the presence of such reducing agents as lithium alumi num hydride. sodium borohydride. potassium borohydride. and the like. Catalysts generally employed in bydrogenation reactions such as. for example. platinum. palladium carbon and Raney nickel may be employed. The reaction is generally carried out in an inert diluent or solvent such as methanol. ethanol. isopropyl alcohol, dioxane and the like. Generally, the reaction is allowed to proceed until the theoretical amount of hydrogen is absorbed. The reaction is carried out at a temperature between and lC, preferably and C.

The salts of the benzothiazole derivatives of the present invention may be prepared by the usual techniques used to prepare acid addition salts of amines. Where the starting compound is already in the form of an acid addition salt. the desired product may be obtained in the form of the corresponding acid salt.

The benzothiazole derivatives and their salts may be incorporated by conventional means into tablets. cap stiles. suspensions. emulsions. solutions or dispersible powders for administration purposes.

The benzothiazole derivatives and their salts may be administered in a dosage from about 0.02 to 1 mg/kg body weight per day. which may be provided in 2 to 4 separate doses at appropriate interval.

The drawings attached hereto show chronotropic and isotropic dose-response curves.

Now. the present invention will be further explained. referring to the following examples. but these examples are merely illustrative and do not restrict the scope of the present invention.

EXAMPLE I A mixture of 40 g of b-hydroxybenzothiazole. g of epichlorohydrin. 55.1 g of potassium carbonate and 800 ml of acetone is refluxed for ll) hours on a water bath.

After cooling. the mixture is subjected to filtration and the filtrate is concentrated. ltltl ml of toluene is added to the concentrate and the mixture is concentrated again. Such a procedure of the addition of toluene and concentration of the mixture is repeated for three times to completely remove the unreacted epichlorohydrine.

As the result. 53.3 g of 3-! b-benzothiazolyloxy )-l.2- epoxypropane is obtained as an oily product. This oily product is dissolved in 600 ml of ethanol and the solution is refluxed together with 160 g of isopropylaniine for 3 hours.

After the reaction. ethanol and isopropylamine are removed by distillation and the residual oily product is dissolved in 300 ml of 3N hydrochloric acid. The resultant acidic solution is washed twice with each ml of ether and then adjusted to a pH of l0 with 3N aqueous solution of sodium hydroxide. The liberated oily product is extracted three times with each 100 ml of ethyl acetate. The ethyl acetate extract is dried with sodium sulfate. After ethyl acetate is removed by distillation. 55 g of solid is obtained. Upon recrystallization of the solid from 3l of ligroin. 43 g of l-(6- benzothiazolyloxy l-3-isopropylamino-Z-propanol is obtained. This substance has a melting point of 97 to 98C. l5 g of this substance is dissolved in 200 ml of ethanol. Upon adding 6N hydrochloric acid solution in ethanol to the resultant solution. the hydrochloride of the desired l-(o-benzothiazolyloxy1-3-isopropylamino- Q-propanol is separated out. Upon recrystallization of 18 g of the crude product from a solvent mixture of 700 ml of isopropylaleohol and 600 ml of ethanol. ll g of white needle crystals is obtained.

Melting point: l32l 34C Elementary analysis as C H N O SHCL3H O:

Calculated: C=43.75 percent. H=7.06 percent. N=7.85 percent. 5 898 percent.

Found: C=43.68 percent. H=6.87 percent, N 7.9O percent. S=9.02 percent.

EXAMPLE 2 3-( 6-benzothiazolyloxy ll .Z-epoxypropane obtained in Example l is reacted with aniline under the same conditions as described in Example 1. After the reaction. l-(6-benzothiazolyloxyl-3-anilino-2propanol hydrochloride is obtained by carrying out the same purification procedure as described in Example l.

Elementary analysis as C .;H ..O N. ,S.HCI.H. ,O

Calculated: C=5-l.l6 percent. H=5.-ltl percent. N=7.89 percent. S=9.()3 percent.

Found: C=54.27 percent. H=5.36 percent. l\'=7.65 percent. S=9.tll percent.

EXAMPLE 3 g of 3-(o-benzotliiazolyloxy ll .Z-epoxypropane obtained in Example I is dissolved in 450 ml of ethanol. 250 g ofisopropylbenzylamine is added to the resultant solution and the mixed solution is refluxed for 3 hours on a water bath.

After the reaction. ethanol and isopropylbenzylamine are removed by distillation and the residual oily product is dissolved in 200 ml of 3N hydrochloric acid. The acidic solution is extracted twice with each IOU ml of ether and adjusted to a pH of lit with 3N aqueous solution of sodium hydroxide. The liberated oily substance is extracted three times with each ltltl ml of ethyl acetate. The ethyl acetate extract is dried with sodium sulfate and the ethyl acetate is removed by distillation. The resultant oily product is dissolved in Hill ml of ethanol. 6N hydrochloric acid solution in ethanol is added to the solution until white crystals cease to separate out of the solution. Thus. crystalline l-(6- benzothiazolyloxy) 3-isopropylbenzylamino-2 propanol hydrochloride is obtained. g ofthe crystals is dissolved in ll of methanol. 5 g of palladium carbon is added to the solution and the mixture is hydrogenated with vigorous stirring at C for 5 hours. The catalyst is then removed by filtration and the filtrate is concentrated. 29.5 g ofcrude l(o-benzothiazolyloxy)- 3-isopropylamino-2-propanol hydrochloride -is obtained. Upon recrystallization of the crude product from a solvent mixture of l.l I of isopropylalcohol and 0.9 l ofethanol. 18.5 g of white needle crystals are obtained.

Melting point: l32l34C Elementary analysis as C H N O SHCL3H O:

Calculated: C=43.75 percent. H=7.06 percent. N=7.85 percent, S=8.98 percent.

Found: C=43.65 percent. H=7.U3 percent. N=7.94 percent, S=8.7l percent.

EXAMPLE 4 30 g of 3-(o-benzothiazolyloxy)-l.2-epoxypropane obtained in Example I is reacted with N-benzylaniline under the same conditions as described in Example 3.

After the reaction. l-(fi-benzothiazolyloxy)-3- benzylanilino-Z-propanol hydrochloride is obtained by carrying out the same purification procedure as described in Example 3. 40 g ofthis substance is dissolved in 1.2 l of methanol. 5 g of palladium carbon is added to the solution and the mixture is hydrogenated with vigorous stirring at C for 6 hours. After the absorption of hydrogen is complete. catalyst is removed by filtration and the filtrate is concentrated. 30.1 g of crude l-(fi-benzothiazolyloxy)-3-anilino-2-propanol hydrochloride is obtained. Upon recrystallization of the ltl crude product front a solvent mixture of l .2 l of isopropanol and l l ofethanol. 19.3 g of white needle crystals are obtained.

Elementary analysis as C H O N SHCLH D:

Calculated: C=5-Ll6 percent. H=5.-ttl percent. l\'=7.89 percent. S=9.03 percent.

Found: C=5-l.l3 percent. H=5.28 percent. l i=7.95 percent. S=8.87 percent.

EXAMPLE 5 A mixture of 20 g of 6-hydroxybenzothiazole. I56 g of l-chloro-R-isopropylamino-2-propanol. 25 g of potassium carbonate and 300 ml of acetone is refluxed at C for 20 hours on a water bath.

After the reaction. potassium carbonate is remo\ ed by filtration and acetone is distilled off. The residue is dissol\ ed in 300 ml of 3N hydrochloric acid. The resul tant solution is naslted three times with each 100 ml of ether and then adjusted to a pH of It) with 3N aqueous solution of sodium hydroxide. The liberated oily product is extracted three times ith each ltll) ml of ethyl acetate. The ethyl acetate extract is dried with sodium sulfate. After ethyl acetate is remoy ed by distillation. 9 g ofsolid is obtained. L'pon recrystallization ofthe solid from 300 ml of ligroin. 8 g of l-t(vbenlothiazolyloxy l- B-isopropylamino2-propanol is obtained.

Melting Point: 97-98C Elementary analysis as C H N O SL Calculated: C=58.63 percent. H=6.h() N=lt).52 percent. S=l 2.0-1 percent.

Found: C=58.44 percent. H=6.8i percent. N=|U.36 percent. 5 12.01 percent.

8 g of this substance is dissolved in 40 ml ot'ethanol. 98 percent sulfuric acid is added to the resultant solution until white crystals cease to separate out of the solution. Upon recrystallization from 250 ml of ethanol. 4.5 g of l-(6-benzothiazolyloxy B-isopropylamino-2 propanol sulfate is obtained as white needle crystals.

Melting point: l34-l35C Elementary analysis as C H N O S.l/2H SO .H O:

Calculated: C=46.83 percent. H=6.35 percent. N=8.4O percent. S=l4.42 percent.

Found: C=46.96 percent. H=6.l2 percent. N=8.3() percent. S=l4.5l percent.

EXAMPLE 6 A mixture of 20 g of 6hydroxybenzothiazole. 220 g of 3-t-butylamino-LZ-oXypropane. 25 g of potassium carbonate and 200 ml of tetrahydrofuran is refluxed at C for l3 hours on a water bath.

After the reaction. potassium carbonate is removed by filtration and tetrahydrofuran is distilled off. The re sidual oily product is dissolved in 300 ml of 3N hydro chloric acid. The resultant solution is washed twice with each 100 ml of ether and then adjusted to a pH of ID with 3N aqueous solution of sodium hydroxide. The liberated oily product is extracted three times with each 100 ml of ethyl acetate. The ethyl acetate extract is dried with sodium sulfate. After ethyl acetate is removed by distillation. 7.5 g of solid is obtained. Upon recrystallization of the solid from a solvent mixture of 20 ml of benzene and 60 ml of ligroin. 6.6 g of l-(6 benzothiazolyloxy)-3-t-butylamino-Z-propanol is obtained.

Melting point: 7475C Elementary analysis as C H- N- O S:

percent.

Calculated: 59.97 percent. H l) percent. N LJ percent. S=l T43 percent.

Found: 59.95 percent. H mm percent. N=9H7 percent. 5 1 l4: percent.

4 g of this substance is dissolved in 50 ml of acetone. A solution of l.7 g otsuccinic acid in 81! ml of acetone is added to the solution. l'pon recrystallization of the crude crystals formed from 50 ml of isopropyl alcohol. 3.8 g of l t o-benzothiazolyloxy )-3-t-but \lamino-I- propanol succinate is obtained.

Elementary analysis as C Hzux OfidlllCH- (OOH l Calculated. Snm percent. N= LI5 percent. 5 945 percent.

Found. C FHTF percent. H ofilts percent. N=8Q7 percent. 9.44 percent.

EXAMPLE 7 4 g of l-lf -ben7otliia2olyloxy I3-amino-Z-propanol and Ill ml of acetone are refluxed for Ill minutes.

After the reaction. acetone is removed by distillation and the residue is dissoh ed in 61) ml of methanol. H) g of sodium borohydride is added little by little to the re sultant solution at room temperature. After the addition. the mixture is refluxed at 65C for 3 hours. The mixture is then cooled and made slightly acidic \vith IN hydrochloric acid. Methanol is removed by distillation and the residue is extracted with (wt) ml ofethyl acetate. The ethyl acetate extract is dried \tith sodium sulfate. After ethyl acetate is removed by distillation. 2.3 g of l-t o-benlothiazoly loxy )-3-isopropylamino-Z-propanol is obtained. Upon recrystallization of this substance from a solvent mixture of 10 ml of benzene and fill ml of ligroin. |.5 g of crystals are obtained.

Melting point: 97-98C Elementary analysis as C H N O S:

Calculated: C=$Xb3 percent. H=o.8() N=ltt52 percent. 8 12.04 percent.

Found: C SSSS percent. H=o.7l percent. N=lll.-l3 percent. S=lltl2 percent.

BETA-ADRENERGIC BLOCKING ACTION AND ANTl-ARRHYTHMIC EFFECT OF l-(o-BENZOTHIAZOLYLOXY )3- ISOPROPYLAMlNOQ-PROPANOL Bet-tradrenergic blocking action of 1-(6- benzothiazoly loxy )-3-isopropylamino-Z-propanol. a benzothiazole derivative of the present invention. is studied in guinea pig atria and tracheal muscle. Antian rhythmic effect on the experimental arrhythmia produced in guinea pig and rat is also examined.

1. Beta-adrenergic blocking action H=ns3 percent.

percent.

Effect on chronotropic response to isoproterenol in isolated guinea pig atrial preparation Male guinea pigs weighing from 300 to 500 g are killed by a blow on the head. The heart is quickly re moved and freed from connective tissues in Krebs- Ringers solution oxygenated with 95 percent 0 and 5 percent C0 Both left and right atria are detached from ventricles. Each end of the atria is ligated with a cotton thread. The preparation is mounted in a ml-organ bath containing oxygenated Krebs-Ringers solution maintained at 37C. One end is fixed and the other is connected with a mechano-electric transducer to measure the atrial contractions. The spontaneous heart rate is measured by means of a pulse rate tachometer. These are recorded on an ink-\vriting oscilloscope.

After an equilibration for one hour. isoproterenol is cumulathely added to the Krebs-Ringer's solution and the doseheart rate relations of the atrial preparation in response to isoproterenol are examined. The prepara tion is then washed repeatedly with Krebs-Ringers solution for 40 minutes. The dose-heart rate relations of the preparation in response to isoproterenol in the presence of 3X10 M l to-benzothiazolyloxy)-3- isopropylamino-Z-propanol (monohydrochloride trihydrate) are also examined in the same manner. Likewise. the doseheart rate relations are examined in the absence and in the presence of 3 l()"M l-(4- methylsultonylaminophenyl )Qdsoporpylaminoethanol which is ell known to have B-adrenergic blocking acti\ity.

FIGS. 1 and 2 respectively shovv the influence of lto bemothiazolyloxy )-3 -isopropylamino-Z-propanol and that of l-[4-methylsulfonylaminophenyll-Z- isopropylaminoethanol on chronotropic dose-response curves to isoproterenol in the guinea pig atria. As is apparent from FlG. l. the dose-response curve shows It) fold parallel shift to the right in the presence of rmhenzothiazolyloxy l-3-isopropylamino-Z-propanol. Nearly the same extent of parallel shift is observed when l-[ 4-methylsulfonylaminophenyl |-1- isopropylaminoethanol is present. The spontaneous heart rate ofthe guinea pig atria which is normally 220 to 131) beats/min. is increased by the application of isoproterenol. Neither of the test drugs alone affects the spontaneous heart rate of the atria. It can be concluded that l-( o-henzothiazolyloxy )-3-isopropylamino-2- propanol exerts a competitive and reversible antagonistic action on isoproterenol in the guinea pig atria and that the potency is almost the same as that of l-(4- methylsu lfonylaminophenyl IZ- isopropylaminoethanol.

Effect on inotropic response to isoproterenol in tracheal muscle of guinea pig Whole tracheal tube is excised from a guinea pig and cut open longitudinally along the anterior side of the trachea. The opened trachea is cut transversely along the ring cartilage into strips of 1.5 to 2 mm in width. Six of these strips are tied up in series to form a chain. The preparation is suspended in an organ bath containing oxygenated Krebs-Ringers solution maintained at 37C. One end of the preparation is fixed and the other end is connected with an isotonic ink-writing lever. The tension applied to the preparation is 0.3 g. The contraction and relaxation of the tracheal chain preparation are isotonically recorded on a kymograph.

lsoproterenol is cumulatively applied to the tracheal chain preparation which is previously contacted with 5 l()""M histamine. The dose-relaxation relations of the trachea in response to isoproterenol are examined in the absence and in the presence of l-(()- benzothiazolyloxy l-3 -is0propylamino-Q-propanol or l-(4methylsulfonylaminophenyl)-2- isopropylaminoethanol.

FIGS. 3 and 4 respectively show the influence of l- (o-benzothiazolyloxyl-3-isopropylamino-2propanol and that of l-t4-methylsulfonylaminophenylJ-Z- isopropylaminoethanol on inotropic dose-response curves to isoproterenol in the guinea pig tracheal muscle. it is apparent from FIG. 3 that as in the case with Table l-Continued Dose of ouabain (pg/kg) tion. it can be concluded that l-((w-benzothiaxolylo y l- Pretreatment No. unequal Fibrillcardiac 3-isopropylamino-B-propanol has B-adrencrgic block- 5 ing activity and that the activity is not significantly dif- 1 l -((-ien/oferent from that of l-(4-methylsultonylannnophen}l) {hm/"M 3 m t l-isopropylaminoethanol. ovy )-3- ll. Anti-arrhythmic effect 222???" 4 1 r v i I i lll l 74 32s Effect on UL11lbt1Ih-lHtillCCd arrhythmia in guinea pig l g 'if in 3st 32s Groups of guinea pigs weighing from 3rd] to 450 g are m 475 used. Each guinea pig is anesthetized bv intraperitoneal 3 1% 2 I94 1 z lnjeCilttll of l 5 g/kg of urethan and 1s cannulated at trapmpvumlul I I chea. l() ug/UJS ml of ouabain is infused into the fe- (1 mg/kg) 4 1:4 3s} moral vein by means of an infusion pump at a rate of 1t) Lg/3 rnin. until death. Five minutes before the start mm" I i oi ouabam infusion. the guinea pigs are treated with 1 mg/kg of l-( 6-benzothiazolyloxy )-3-isopropylaminoJ- t '7 propanol or mg/kg of propranolol by Intravenous in- V v jection. Each of the test drugs is dissolved in l nil/kg of Eflect cdcle'mduckll i' mi saline solution. As a control. 1 ml/kg of saline solution Gruups H i hi 350 m 4 g arc usulv E h i imfllwlmusl) "\l P 8 l The rat is anesthetized by intraperitoneal injection of i5 decimcllrdiogmm l5 reclrdfid mkwmmg N g/kg of urethan and cannulated at trachea. A solution l0Stope i high gum DC dmpmlcr and n of 200 mg/ml of CiJC i-z in water is infused into the fefects ofthe test drugs on cardiotoxicity of ouabain are in by an infusion pump at a rate of 0.35 studied. nil/min. until death. The rats are pretreated with 1 When ouabain is administered to guinea pigs. the first /kg or 10 mg/kg of l-( o-benzothiazolyloxy)-3 indication of its activity is a decrease in the spontanem j -l; i '1 or 1 mg/kg or 5 mg/kg of ous heart rate. followed by a prolongation of the P-R propranolol five minutes before the start of CaCl inf in r lll (Unequal interval). As the administration prosion. The drugs are dissolved in l rnl/kg of saline soluceeds. extrasystoles are observed and subsequently. tion and intravenously injected. As a control. the rats venticular fibrillation and cardiac arrest occur. At each of one group are treated with l nil/kg of saline solution. of these successive sta es of intoxication. the amount The effects ofthe test drues on cardiotoxic action of 3s of ouabain administered IS checked on The effects of C CI are det rm ned by measuring the time (second) the test drugs are determined by the amount of ouabain from the start of the infusion of CaCl until death. The administered. death of rats by the administration of CaCl can be at- The results are shown in Table 1 below. It is apparent tributed to a cardiac arrest The results are shown in from the table that l-((i-benzothiazolyloxy)-3- 4 Table 2. From the table. it is apparent that H6- isopropylamino-Z-propanol has an antfcardiotoxic efbenzothiazolyloxy)-3-isopropylamino-Z-propanol has a feet against ouabain which is comparable to that ofprocardiotoxic effect against CaCl and the potency 1s pranolol. comparable to that of propranololr Table 2 Time of Catf'l infusion until death (sec) Pretreatment No l 2 3 4 5 (i mean Control (saline) I97 186 I 23h Ztll) I92 l-(o-benzothiazolyloxy l mg/kg) 302 240 280 221 212 25] 3-isopropylamino-l propanol (ll) lug/kg) 325 225 I68 183 25-1 281) 239 (1 mg/kg) I75 260 :07 286 I95 225 Propanolol (5 mg/kg) 263 IN) lS-L 262 222 Table I What is claimed is:

l. A compound of the formula Dose of ouabain lug/kg) 6U Pretreatment No. unequal Fibrillcardiac intenal ation arrest 1 ns I52 um N 2 66 I724 206 Control (saline) 3 8h Z 34H 4 213 246 S O H H H mean vs 207 23:: c 2 0 Z )25 288 33s 2 29| 328 OH fill wherein said compound is in the form of the hydrochloride salt thereof.

4. The compound of claim 1 wherein R is isopropylbenzyli 5. The compound of claim 1 wherein R is isopropyl and wherein said compound is in the form ofthe sulfate salt thereof.

6. The compound of claim I wherein R is t-hutyl.

7. The compound of claim 6, wherein said compound is in the form of the succinate salt thereof. 

1. A COMPOUND OF THE FORMULA 6-(R-NH-CH2-CH(-OH)-CH2-O-)BENZOTHIAZOLE WHEREIN R IS HYDROCARBON GROUP SELECTED FROM THE GROUP CONSISTING OF ALKYL GROUPS HAVING 1 TO 5 CARBON ATOMS, ARALKYL GROUPS HAVING 7 TO 10 CARBON ATOMS AND ARYL GROUPS HAVING 6 TO 10 CARBON ATOMS, AND ACID ADDITION SALTS THEREOF, SAID ACID ADDITION SALTS BEING SELECTED FROM THE GROUP CONSISTING OF HYDROCHLORIDE, HYDROBROMIDE, PHOSPHATE, SULFATE, NITRATE, OXALATE, LACTATE, TARTRATE, ADIPATE, ACETATE, PROPIONATE, SALICYLATE, CITRATE, MALEATE, NAPHTHOATE, SUCCINATE AND BENZOATE SALTS THEREOF.
 3. The compound of claim 1 wherein R is phenyl and wherein said compound is
 5. The compound of claim 1 wherein R is isopropyl and wherein said compound
 7. The compound of claim 6, wherein said compound is in the form of the succinate salt thereof. 